Tissues lined by squamous epithelial cells are regularly exposed to a large number of infectious and non-infectious insults. As a result, the protective epithelium has evolved a series of innate defense mechanisms to maintain an equilibrium between normal tissue function and unwarranted tissue destruction. An exquisite example is the esophagus. The esophageal mucosa utilizes a number of protective mechanisms including peristalsis, mucous secretion, and bicarbonate exchange to minimize the influence of potential injurious agents. In addition, the healthy squamous epithelium contains a number of immunocytes including mast cells, lymphocytes and dendritic cells. Conversely, esophageal diseases also lead to significant morbidity including gastroesophageal reflux disease (GERD) and esophageal cancer, with a disease frequency of nearly 25 million U.S. citizens per year. A common marker for esophageal inflammation is the accumulation of eosinophils. Our recent studies have examined the influenced of eosinophil derived granule protein major basic protein (MBP) can significantly influence epithelial structure and function. It is not known whether eosinophils represent a "friend" or "foe" in esophageal inflammation. To begin to address this issue, we utilized gene chip analysis and determined that MBP markedly induced the synthesis of an innate molecule of defense, bactericidal permeability-increasing protein (BPI), a potent anti-infective molecule with microbial killing and endotoxin-neutralizing functions, with previous expression attributed only to leukocytes. Ongoing and endotoxin-neutralizing functions, with previous expression attributed only to leukocytes. Ongoing studies have: a) revealed that squamous epithelial express BPI, b) identified the BPI gene promoter and it's expression in squamous epithelia, and c) identified a murine homolog of BPI expressed in mucosal epithelia. From these preliminary data, we hypothesize that squamous epithelial BPI is central to esophageal responses to eosinophilic disease. Two specific aims are directed at testing this hypothesis. Specific Aim 1: Define molecular mechanisms of BPI expression in squamous epithelia. Preliminary data indicate that epithelial BPI is functionally relevant in bacterial killing and in control of endotoxin responses in epithelia. At present, essentially nothing is known about the factor(s) which regulate BPI expression. Ongoing studies have identified and characterized the BPI gene promoter, and here we propose to gain insight into how squamous epithelial BPI expression is regulated at the molecular level. Specifically, we will elucidate molecular determinants of BPI promoter constructs. Specific Aim 2: Characterize squamous epithelial expression of the BPI homolog in healthy and eosinophilic diseased murine tissue. Until recently, it was believed that mice did not express BPI. New data from the Mouse Genome Project identified a BPI homolog on chromosome 1, and our ongoing work has revealed that mouse epithelia express BPI. In these studies, we will extend these preliminary findings to profile squamous epithelial BPI expression in the esophagus, define expression of BPI in murine esophagitis animals, and examine BPI expression in human patient esophageal tissue. The long-term goal of this research is to elucidate the role of epithelial BPI in health and disease. A better understanding of these principles provide the potential for therapies aimed at ameliorating symptoms associated with mucosal infection and inflammation.